Having high fasting glucose levels is one of the most perplexing characteristics of type 2 diabetes mellitus patients. This is because the liver produces glucose in these insulin-resistant people, a mechanism that still raises many unanswered issues for scientists.
An extensive summary of the most significant
developments in comprehending this process is now provided in a review paper
that was published in the journal Trends in Endocrinology & Metabolism.
Additionally, it aids in the discovery of novel
therapeutic targets in the battle against type 2 diabetes mellitus, which the
World Health Organization (WHO) lists as one of the pandemics of the
twenty-first century.
The study is led by Professor Manuel
Vazquez-Carrera, from the Faculty of Pharmacy and Food Sciences of the
University of Barcelona, the UB Institute of Biomedicine (IBUB), the Sant Joan
de Deu Research Institute (IRSJD) and the Centre for Biomedical Research
Network on Diabetes and Associated Metabolic Diseases (CIBERDEM). Among the
participants in the study are the experts Emma Barroso, Javier Jurado-Aguilar
and Xavier Palomer (UB-IBUB-IRJSJD-CIBERDEM) and Professor Walter Wahli, from
the University of Lausanne (Switzerland).
Therapeutic targets to fight the disease
Type 2 diabetes mellitus is an increasingly
common chronic disease that results in high levels of circulating glucose --
the cellular energy fuel -- due to a deficient insulin response in the body. It
can cause severe organ damage and is estimated to be under-diagnosed in a high
percentage of the affected population worldwide.
In patients, the glucose synthesis pathway in
the liver (gluconeogenesis) is hyperactivated, a process that can be controlled
by drugs such as metformin. "Recently, new factors involved in the control
of hepatic gluconeogenesis have been identified. For example, a study by our
group revealed that growth differentiation factor (GDF15) reduces the levels of
proteins involved in hepatic gluconeogenesis", said Professor Manuel
Vazquez-Carrera, from the UB's Department of Pharmacology, Toxicology and
Therapeutic Chemistry.
To make progress in the fight against this
pathology, it will also be necessary to further study pathways such as TGF-b,
which is involved in the progression of metabolic dysfunction-associated fatty
liver disease (MASLD), a very prevalent pathology that often coexists with type
2 diabetes mellitus. "TGF-b plays a very relevant role in the progression
of liver fibrosis and has become one of the most important factors that may
contribute to increased hepatic gluconeogenesis and, therefore, to type 2
diabetes mellitus. Therefore, studying the involvement of the TGF-b pathway in
the regulation of hepatic gluconeogenesis could help to achieve better
glycaemic control", stresses Vazquez-Carrera.
However, acting on a single factor to improve
the regulation of gluconeogenesis does not seem to be a sufficient therapeutic
strategy to adequately control the disease.
"It would be important to be able to design
combination therapies that could consider the different factors involved to
improve the approach to type 2 diabetes mellitus", Vazquez-Carrera said.
"Today there are several molecules --
TGF-b, TOX3, TOX4, etc. -- that could be considered therapeutic targets for
designing future strategies to improve patients' well-being. Their efficacy and
safety will determine their therapeutic success. We cannot lose sight of the
fact that controlling the overactivation of hepatic gluconeogenesis in type 2
diabetes mellitus has an additional difficulty: it is a key pathway for making
glucose available in fasting situations, it is finely modulated by numerous
factors and this makes regulation difficult", he adds.
Interestingly, other factors involved in the
control of gluconeogenesis have also been identified in patients hospitalised
with COVID-19 who showed high glucose levels. "Hyperglycaemia was very
prevalent in patients hospitalised with COVID-19, which seems to be related to
the ability of SARS-CoV-2 to induce the activity of proteins involved in
hepatic gluconeogenesis", the expert notes.
Metformin: the unknowns of the most prescribed
drug
The mechanisms of action of metformin, the most
commonly prescribed drug for the treatment of type 2 diabetes, which reduces
hepatic gluconeogenesis, are still not fully understood. It has now been
discovered that the drug decreases gluconeogenesis via inhibition of complex IV
of the mitochondrial electron transport chain. This is a mechanism independent
of the classical effects known until now through activation of the AMPK
protein, a sensor of the cell's energy metabolism.
"Inhibition of mitochondrial complex IV
activity by metformin -- not complex I as previously thought -- reduces the
availability of substrates required for hepatic glucose synthesis", said
Vazquez-Carrera.
In addition, metformin can also reduce
gluconeogenesis through its effects on the gut, leading to changes that
ultimately attenuate hepatic glucose production in the liver. "Thus,
metformin increases glucose uptake and utilisation in the gut, and generates
metabolites capable of inhibiting gluconeogenesis when they reach the liver via
the portal vein. Finally, metformin also stimulates the secretion of GLP-1 in
the intestine, a hepatic gluconeogenesis inhibitory peptide that contributes to
its anti-diabetic effect", he explained.
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